Manganese (II) chelate manufacture

Abstract

The process of this invention for preparing Mn(II) chelate comprises forming the Mn(II) chelate by mixing manganese(II) oxide (insoluble) with an aqueous suspension comprising a molar equivalent or molar excess of the insoluble protonated chelating compound at a temperature of from 20 DEG to 50 DEG C. When the reaction is carried out with a protonated chelating agent in the absence of base, a precipitate of the protonated Mn(II) chelate is formed. A low osmolarity Mn(II) chelate solution can be formed from the precipitates by dissolving them in an aqueous solution of base. When the initial chelate forming reaction is carried out in a solution containing a molar equivalent or excess of sodium hydroxide, a low osmolarity solution of the Mn(II) chelate is directly formed with most chelating agents. Preferred chelating compounds for this process include DPDP, DTPA, DCTA, EDTP, DOTA, DOXA, DO3A and EDTA. The Mn(II) chelate precipitates and low osmolarity solutions formed by the above processes are also aspects of this invention.

We claim: 
     
       1. A process for manufacturing Mn(II) chelates comprising reacting a substantially protonated, insoluble chelating compound having acidic protons with MnO in water to form a substantially protonated Mn(II) chelate precipitate, with the proviso that the chelating compound is a compound other than EDTA or DTPA. 
     
     
       2. The process of claim 1 wherein the reaction is carried out at a temperature of from 20 to 50° C., and the MnO is reacted with at least one molar equivalent of the chelating compound. 
     
     
       3. The process of claim 1 including the step of dissolving the Mn(II) chelate precipitate in an aqueous solution of base. 
     
     
       4. The process of claim 3 wherein the base is a pharmaceutically acceptable base. 
     
     
       5. The process of claim 1 wherein the chelating compound is a compound of Formula I, the corresponding pharmaceutically acceptable salts thereof, or the phosphate group mono and diesters thereof with mono and polyhydric alkanols having from 18 carbons, or alkylamino alcohols, each having from 1 to 18 carbons. ##STR13## wherein R 1  is hydrogen or ##STR14## R 2  is hydrogen or ##STR15## and one of R 1  and R 2  is other than hydrogen; R 3  is alkylene having from 5 to 8 carbons, 1,2-cycloalkylene having from 5 to 8 carbons, or 1,2-arylene having from 6 to 10 carbons, and R 4  is hydrogen, alkyl having from 1 to 6 carbons, or ##STR16## R 5  and R 6  are each, individually, hydroxy, alkoxy having are each, individually, hydroxy, alkoxy having from 1 to 18 carbons, hydroxy-substituted alkoxy having from 1 to 18 carbons, amino or alkylamido having from 1 to 18 carbons.   
     
     
       6. The process of claim 5 wherein the chelating compound is DPDP. 
     
     
       7. The process of claim 1 wherein the chelating compound is a compound of Formula II or a pharmaceutically acceptable salt thereof: ##STR17## wherein R 7  is hydroxy, alkoxy having from 1 to 18 carbons, hydroxy-substituted alkoxy having from 1 to 18 carbons, amino or alkylamido having from 1 to 18 carbons; R 8  is hydrogen or ##STR18## R 9  is hydroxy, alkoxy having from 1 18 carbons, hydroxy-substituted alkoxy having from 1 to 18 carbons, amino or alkylamido having from 1 to 18 carbons; and   R 10  alkylene having from 1 to 8 carbons, 1,2-cycloalkkylene having from 5 to 8 carbons, or 1,2-arylene having from 6 to 10 carbons.   
     
     
       8. The process of claim 1 wherein the chelating compound is a compound of Formula III or (CH 2  X) 3  : ##STR19## wherein X is --COOY, PO 3  HY or --CONHOY; Y is a hydrogen atom, a metal ion equivalent and/or a basic biocompatible cation of an inorganic or organic base or basic amino acid;   A is ##STR20## wherein X is as defined above;   each of R 11  is hydrogen or methyl;   R 12  and R 13  together represent an alkylene group having from 1 to 8 carbons (e.g., trimethylene, tetramethylene, etc.), or individually are hydrogen atoms, lower alkyl groups (e.g., 1-8 carbon atoms), phenyl groups, or benzyl groups;   m represents the number 1, 2 or 3;   Z is an oxygen atom or a sulfur atom or the group ##STR21## wherein X is as defined above; and   R 14  is a lower alkyl group (e.g., 1-8 carbon atoms);   V has the same meaning as X, or is   --CH.sub.2 OH or --CONH(CH.sub.2).sub.n X ,     wherein     X is as defined above;   n is an integer of from 1 to 12;   or if R 11 , R 12  and R 13  are hydrogen atoms, both V's together are the group ##STR22## wherein X is as defined above,   w is the number 1, 2 or 3.   
     
     
       9. The process of claim 1 wherein the chelating compound is a compound of Formula IV: ##STR23## wherein Y 1  is oxygen or ##STR24## R 20  is hydrogen, alkyl, arylalkyl or aryl; and R 21  is hydrogen, alkyl, hydroxyalkyl or carboxyalkyl. 
     
     
       10. The process of claim 9 wherein the chelating compound is DOXA of DO3A. 
     
     
       11. The process of claim 1 wherein the chelating compound is DPDP, DCTA, EDTP, DOTA, DO3A or DOXA. 
     
     
       12. A process for manufacturing an aqueous Mn (II) chelate solution comprising reacting a soluble chelating compound having acidic protons with MnO in water in the presence of a quantity of a pharmaceutically acceptable base which is sufficient to yield a Mn(II) chelate solution with the proviso that the chelating compound is a compound other than EDTA or DTPA. 
     
     
       13. The process of claim 12 wherein the reaction is carried out in water in the presence of from 1 to 6 molar equivalents of base. 
     
     
       14. The process of claim 12 wherein the cation of the pharmaceutically acceptable base is lithium, sodium, potassium, calcium, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucmine, N-methylglucamine, lysine, arginine or orithine. 
     
     
       15. The process of claim 12 wherein the chelating compound is DPDP, DCTA, EDTP, DOXA DO3A or DOTA. 
     
     
       16. The process of claim 15 wherein the chelating compound is DPDP.